Receptor-receptor interactions in heteroreceptor complexes: a new principle in biology. Focus on their role in learning and memory

The allosteric receptor-receptor interactions over the interfaces in heteroreceptor complexes have beenexplored and their biochemical, pharmacological and functional integrative implications in the CentralNervous System (CNS) described. GPCR interacting proteins participate in these complexes mainlythrough modulation of receptor-receptor interactions. Methodologies to study heteroreceptor complexesin living cells (FRET and BRET-based techniques) and in brain tissue (in situ proximity ligation assay)are briefly summarized. The physiological and pathological relevance of the allosteric receptor-receptorinteractions in heteroreceptor complexes is emphasized and novel strategies for treatment of mentaland neurological disease are developed based on this new biological principle of integration. Themolecular basis of learning and memory is proposed to be based on the reorganization of the homo- andheteroreceptor complexes in the postjunctional membrane of synapses leading also to changes in theprejunctional receptor complexes to facilitate the pattern of transmitter release to be learned. Long-termmemory may be created by the transformation of parts of the heteroreceptor complexes into uniquetranscription factors which can lead to the formation of specific adapter proteins which can consolidatethe heteroreceptor complexes into long-lived complexes with conserved allosteric receptor-receptorinteractions